Dr. Akintoye's commitment to research and academic dentistry have prepared him for a career as an independent Clinician-Scientist at the School of Dental Medicine, University of Pennsylvania. This K08 application, under the mentorship of Drs. Phoebe Leboy and Marjorie Jeffcoat, seeks to apply bone marrow stromal cell (BMSC) technology to treat osteoradionecrosis and provide training in translational research. In the oro-facial region, osteoradionecrosis is a major complication of head and neck cancer radiotherapy characterized by tissue dehiscence, bone exposure, facial deformities, compromised oro-facial function and diminished quality of life. Current non-surgical treatment of osteoradionecrosis is hyperbaric oxygen therapy that improves tissue oxygenation transiently. The results are variable as healing is incomplete, it is contra-indicated in some patients and subsequent surgical resection of affected bones is often needed. Clinical data indicate that maxillofacial reconstruction with autologous graft from the axial bones to bridge osseous jaw defects often results in non-integration and graft resorbtion, while grafting bone from other oro-facial sites is usually more successful. Similarly, diseases such as cherubism and hyperparathyroid jaw tumor syndrome are restricted to the jaw bones and never been described in other sites. These properties unique to the jaw bones still remain unclear and need to be further elucidated. They may be related to the different embryological origins of the craniofacial (neural crest origin) and axial (mesodermal origin) bones, but anatomic skeletal site-specific properties of human BMSC have not been conclusively defined. Regeneration of new bone in radionecrotic bone using grafted ex vivo expanded BMSC from different skeletal sites has also not been explored either in humans or animals. Dr. Akintoye has proposed in the first specific aim to investigate site-specific distinctive osteogenic properties and radiosensitivity of human BMSC of the maxilla and mandible (neural crest origin) and ilium (mesodermal origin). The second specific aim will elucidate site-specific regenerative properties of human BMSC in spontaneous osteoradionecrosis in athymic rats. By transplanting normal human BMSC from mandible and iliac crest, he will study and compare their efficacy as graft to heal osteoradionecrosis. New methods are needed to treat osseous defects; we propose the use of tissue engineering technology (ex vivo expanded BMSC) to treat osteoradionecrosis, a recalcitrant clinical problem associated with head and neck cancer radiotherapy. These data will provide substantial new insights. Dr. Akintoye's long term goal is to ultimately translate these into human clinical protocols to treat patients with osteoradionecrosis. [unreadable] [unreadable] [unreadable]